tbuckley/cabot-search huggingface dataset:
Nucleic acid-based therapy for brain cancer: Challenges and strategies
Authors: Zixia Zhang, João Conniot, Joana Amorim, Yiliang Jin, Rajendra Prasad, Xiyun Yan, Kelong Fan, João Conde
Journal: Journal of Controlled Release (2022)

Nucleic acid-based therapy emerges as a powerful weapon for the treatment of tumors thanks to its direct, effective, and lasting therapeutic effect. Encouragingly, continuous nucleic acid-based drugs have been approved by the Food and Drug Administration (FDA) and the European Medicines Agency (EMA). Despite the tremendous progress, there are few nucleic acid-based drugs for brain tumors in clinic. The most challenging problems lie on the instability of nucleic acids, difficulty in traversing the biological barriers, and the off-target effect. Herein, nucleic acid-based therapy for brain tumor is summarized considering three aspects: (i) the therapeutic nucleic acids and their applications in clinical trials; (ii) the various administration routes for nucleic acid delivery and the respective advantages and drawbacks. (iii) the strategies and carriers for improving stability and targeting ability of nucleic acid drugs. This review provides thorough knowledge for the rational design of nucleic acid-based drugs against brain tumor.
The Impact of the COVID-19 Pandemic on Ethnic Minority Groups With Diabetes
Authors: Kamlesh Khunti, Eva L. Feldman, Neda Laiteerapong, William Parker, Ash Routen, Monica Peek
Journal: Diabetes Care (2022)

Major ethnic disparities in diabetes care, especially for intermediate outcomes and diabetes complications, were evident prior to the coronavirus disease 2019 (COVID-19) pandemic. Diabetes is a risk factor for severe COVID-19, and the combination of these ethnic disparities in diabetes care and outcomes may have contributed to the inequity in COVID-19 outcomes for people with diabetes. Overall, ethnic minority populations have suffered disproportionate rates of COVID-19 hospitalization and mortality. Results from the limited number of studies of COVID-19 in ethnic minority populations with diabetes are mixed, but there is some suggestion that rates of hospitalization and mortality are higher than those of White populations. Reasons for the higher incidence and severity of COVID-19–related outcomes in minority ethnic groups are complex and have been shown to be due to differences in comorbid conditions (e.g., diabetes), exposure risk (e.g., overcrowded living conditions or essential worker jobs), and access to treatment (e.g., health insurance status and access to tertiary care medical centers), which all relate to long-standing structural inequities that vary by ethnicity. While guidelines and approaches for diabetes self-management and outpatient and inpatient care during the pandemic have been published, few have recommended addressing wider structural issues. As we now plan for the recovery and improved surveillance and risk factor management, it is imperative that primary and specialist care services urgently address the disproportionate impact the pandemic has had on ethnic minority groups. This should include a focus on the larger structural barriers in society that put ethnic minorities with diabetes at potentially greater risk for poor COVID-19 outcomes.
Transoral Robotic Surgery for Recurrent Tumors of the Upper Aerodigestive Tract (RECUT): An International Cohort Study
Authors: John C Hardman, F Chris Holsinger, Grainne C Brady, Avinash Beharry, Alec T Bonifer, Gregoire D’Andréa, Surender K Dabas, John R de Almeida, Umamaheswar Duvvuri, Peter Floros, Tamer A Ghanem, Philippe Gorphe, Neil D Gross, David Hamilton, Chareeni Kurukulasuriya, Mikkel Hjordt Holm Larsen, Daniel J Lin, J Scott Magnuson, Jeroen Meulemans, Brett A Miles, Eric J Moore, Gouri Pantvaidya, Scott Roof, Niclas Rubek, Christian Simon, Anand Subash, Michael C Topf, Kathryn M Van Abel, Vincent Vander Poorten, Evan S Walgama, Emily Greenlay, Laura Potts, Arun Balaji, Heather M Starmer, Sarah Stephen, Justin Roe, Kevin Harrington, Vinidh Paleri
Journal: JNCI Journal of the National Cancer Institute (2022)

Abstract Background Transoral robotic surgery (TORS) is an emerging minimally invasive surgical treatment for residual, recurrent, and new primary head and neck cancers in previously irradiated fields, with limited evidence for its oncological effectiveness. Methods A retrospective observational cohort study of consecutive cases performed in 16 high-volume international centers before August 2018 was conducted (registered at clinicaltrials.gov [NCT04673929] as the RECUT study). Overall survival (OS), disease-free survival, disease-specific survivals (DSS), and local control (LC) were calculated using Kaplan-Meier estimates, with subgroups compared using log-rank tests and Cox proportional hazards modeling for multivariable analysis. Maximally selected rank statistics determined the cut point for closest surgical resection margin based on LC. Results Data for 278 eligible patients were analyzed, with median follow-up of 38.5 months. Two-year and 5-year outcomes were 69.0% and 62.2% for LC, 71.8% and 49.8% for OS, 47.2% and 35.7% for disease-free survival, and 78.7% and 59.1% for disease-specific survivals. The most discriminating margin cut point was 1.0 mm; the 2-year LC was 80.9% above and 54.2% below or equal to 1.0 mm. Increasing age, current smoking, primary tumor classification, and narrow surgical margins (≤1.0 mm) were statistically significantly associated with lower OS. Hemorrhage with return to theater was seen in 8.1% (n = 22 of 272), and 30-day mortality was 1.8% (n = 5 of 272). At 1 year, 10.8% (n = 21 of 195) used tracheostomies, 33.8% (n = 66 of 195) used gastrostomies, and 66.3% (n = 53 of 80) had maintained or improved normalcy of diet scores. Conclusions Data from international centers show TORS to treat head and neck cancers in previously irradiated fields yields favorable outcomes for LC and survival. Where feasible, TORS should be considered the preferred surgical treatment in the salvage setting.
Mitochondrial calcium and reactive oxygen species in cardiovascular disease
Authors: Elizabeth Murphy, Julia C Liu
Journal: Cardiovascular Research (2022)

Abstract Cardiomyocytes are one of the most mitochondria-rich cell types in the body, with ∼30–40% of the cell volume being composed of mitochondria. Mitochondria are well established as the primary site of adenosine triphosphate (ATP) generation in a beating cardiomyocyte, generating up to 90% of its ATP. Mitochondria have many functions in the cell, which could contribute to susceptibility to and development of cardiovascular disease (CVD). Mitochondria are key players in cell metabolism, ATP production, reactive oxygen species (ROS) production, and cell death. Mitochondrial calcium (Ca2+) plays a critical role in many of these pathways, and thus the dynamics of mitochondrial Ca2+ are important in regulating mitochondrial processes. Alterations in these varied and in many cases interrelated functions play an important role in CVD. This review will focus on the interrelationship of mitochondrial energetics, Ca2+, and ROS and their roles in CVD. Recent insights into the regulation and dysregulation of these pathways have led to some novel therapeutic approaches.
Effect of Different Drinks on Fluid and Electrolyte Losses from a Jejunostomy
Authors: C R Newton, P B McIntyre, J E Lennard-Jones, J J Gonvers, D M Preston
Journal: Journal of the Royal Society of Medicine (1985)

The effectiveness of 5 different solutions on the absorption of fluid and electrolytes was tested in 7 patients with a proximal intestinal stoma and large fluid losses, all of whom previously needed intravenous infusions to maintain balance. In 4 patients it proved possible to replace the intravenous infusions with an enteral supplement. The WHO glucose/electrolyte solution without added potassium (NaCl 3.5 g, NaHCO3 2.5 g, glucose 20 g/l) gave satisfactory results, though was slightly less effective than a solution containing more sodium in which maltose was substituted for glucose. Neither sucrose nor an oligosaccharide (Caloreen) gave an advantage over glucose in the formulations used. In 3 patients losses were so great, and absorption of sodium from oral solutions so small, that intravenous supplements had to be continued. These 3 patients could be distinguished from the other 4 by the fact that more than 250 ml emerged from the stoma during the 3 hours after a drink of 500 ml of glucose/electrolyte solution. In all patients a drink of water or tea led to a loss of sodium from the stoma; water should be restricted in such patients and replaced by a glucose/electrolyte solution.
Interstitial Photothermal Therapy Generates Durable Treatment Responses in Neuroblastoma
Authors: Debbie K. Ledezma, Preethi B. Balakrishnan, Anshi Shukla, Jacob A. Medina, Jie Chen, Emily Oakley, Catherine M. Bollard, Gal Shafirstein, Mario Miscuglio, Rohan Fernandes
Journal: Advanced Healthcare Materials (2022)

Photothermal therapy (PTT) represents a promising modality for tumor control typically using infrared light-responsive nanoparticles illuminated by a wavelength-matched external laser. However, due to the constraints of light penetration, PTT is generally restricted to superficially accessible tumors. With the goal of extending the benefits of PTT to all tumor settings, interstitial PTT (I-PTT) is evaluated by the photothermal activation of intratumorally administered Prussian blue nanoparticles with a laser fiber positioned interstitially within the tumor. This interstitial fiber, which is fitted with a terminal diffuser, distributes light within the tumor microenvironment from the "inside-out" as compared to from the "outside-in" traditionally observed during superficially administered PTT (S-PTT). I-PTT improves the heating efficiency and heat distribution within a target treatment area compared to S-PTT. Additionally, I-PTT generates increased cytotoxicity and thermal damage at equivalent thermal doses, and elicits immunogenic cell death at lower thermal doses in targeted neuroblastoma tumor cells compared to S-PTT. In vivo, I-PTT induces significantly higher long-term tumor regression, lower rates of tumor recurrence, and improved long-term survival in multiple syngeneic murine models of neuroblastoma. This study highlights the significantly enhanced therapeutic benefit of I-PTT compared to traditional S-PTT as a promising treatment modality for solid tumors.
Author Correction: Long-term safety and efficacy of lentiviral hematopoietic stem/progenitor cell gene therapy for Wiskott–Aldrich syndrome
Authors: A. Magnani, M. Semeraro, F. Adam, C. Booth, L. Dupré, E. C. Morris, A. Gabrion, C. Roudaut, D. Borgel, A. Toubert, E. Clave, C. Abdo, G. Gorochov, R. Petermann, M. Guiot, M. Miyara, D. Moshous, E. Magrin, A. Denis, F. Suarez, C. Lagresle, A. M. Roche, J. Everett, A. Trinquand, M. Guisset, J. Xu Bayford, S. Hacein-Bey-Abina, A. Kauskot, R. Elfeky, C. Rivat, S. Abbas, H. B. Gaspar, E. Macintyre, C. Picard, F. D. Bushman, A. Galy, A. Fischer, E. Six, A. J. Thrasher, M. Cavazzana
Journal: Nature Medicine (2022)
<i>In Utero</i> and Childhood/Adolescence Exposure to Tobacco Smoke, Genetic Risk, and Lung Cancer Incidence and Mortality in Adulthood
Authors: Heng He, Ming-Ming He, Haoxue Wang, Weihong Qiu, Lei Liu, Lu Long, Qian Shen, Shanshan Zhang, Shifan Qin, Zequn Lu, Yimin Cai, Ming Zhang, Siyuan Niu, Jiaoyuan Li, Na Shen, Ying Zhu, Jianbo Tian, Jiang Chang, Xiaoping Miao, Rong Zhong
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

The individual effects of early-life tobacco smoke exposure and its interactions with genetic factors on lung cancer in adulthood remain unclear.
Voltage-Gated Sodium Channel Na<sub>V</sub>1.8 Dysregulates Na and Ca, Leading to Arrhythmias in Patients with Sleep-Disordered Breathing
Authors: Simon Lebek, Philipp Hegner, Rosa Hultsch, Jonas Rohde, Leopold Rupprecht, Christof Schmid, Samuel Sossalla, Lars Siegfried Maier, Michael Arzt, Stefan Wagner
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Voltage-Gated Sodium Channel NaV1.8 Dysregulates Na and Ca, Leading to Arrhythmias in Patients with Sleep-Disordered Breathing." American Journal of Respiratory and Critical Care Medicine, 206(11), pp. 1428–1431
Matrix Metalloproteinase-12 Supports Pulmonary B Cell Follicle Formation and Local Antibody Responses During Asthma
Authors: Chloe J. Pyle, Dhiren F. Patel, Teresa Peiró, Régis Joulia, Aleksander M. Grabiec, Tracy Hussell, Gael Tavernier, Angela Simpson, James Pease, James A. Harker, Clare M. Lloyd, Robert J. Snelgrove
Journal: American Journal of Respiratory and Critical Care Medicine (2022)
Use of the Steno T1 Risk Engine Identifies Preclinical Atherosclerosis Better Than Use of ESC/EASD-2019 in Adult Subjects With Type 1 Diabetes at High Risk
Authors: Tonet Serés-Noriega, Marga Giménez, Verónica Perea, Laura Boswell, Clara Viñals, Jesús Blanco, Irene Vinagre, Adriana Pané, Enric Esmatjes, Ignacio Conget, Antonio J. Amor
Journal: Diabetes Care (2022)

OBJECTIVE To evaluate the concordance between the 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD (ESC/EASD-2019) and the Steno T1 Risk Engine (Steno-Risk) cardiovascular risk scales for individuals with type 1 diabetes (T1D) without cardiovascular disease (CVD) and to analyze the relationships of their use with identification of preclinical atherosclerosis. RESEARCH DESIGN AND METHODS We consecutively selected patients with T1D, without CVD, age ≥40 years, with nephropathy, and/or with ≥10 years of T1D evolution with another risk factor. The presence of plaque at different carotid segments was determined by ultrasonography. Cardiovascular risk was estimated in accord with ESC/EASD-2019 risk groups (moderate/high/very high) and the Steno-Risk (&amp;lt;10%, low; 10–20%, moderate; ≥20%, high), as T1D-specific scores. In an exploratory analysis, we also evaluated the non-T1D-specific 2013 ACC/AHA Guideline on the Assessment of Cardiovascular Risk (ACC/AHA-2013) pooled cohort equation for individuals between 40 and 79 years of age. RESULTS We included 501 patients (53% men, mean age 48.8 years, median T1D duration 26.5 years, 41.3% harboring plaques). Concordance between T1D-specific scales was poor (κ = 0.19). A stepped increase in the presence of plaques according to Steno-Risk category was seen (18.4%, 38.2%, and 64.1%, for low, moderate, and high risk, respectively; P for trend &amp;lt;0.001), with no differences according to ESC/EASD-2019 (P = 0.130). Steno-Risk identified individuals with plaques, unlike ESC/EASD-2019 (area under the curve [AUC] 0.691, P &amp;lt; 0.001, vs. AUC 0.538, P = 0.149). Finally, in polynomial regression models (with adjustment for lipid parameters and cardioprotective treatment), irrespective of the ESC/EASD-2019 category, high risk by Steno-Risk was directly associated with atherosclerosis (in moderate/high-risk by ESC/EASD-2019 odds ratio 2.91 [95% CI 1.27–6.72] and 4.94 [2.35–10.40] for the presence of plaque and two or more plaques). Similar results were obtained with discordant higher Steno-Risk versus ACC/AHA-2013 (P &amp;lt; 0.001). CONCLUSIONS Among T1D patients undergoing primary prevention, use of Steno-Risk seems to result in better recognition of individuals with atherosclerosis in comparison with ESC/EASD-2019. Notwithstanding, carotid ultrasound could improve the categorization of cardiovascular risk.
COVID-19 Exacerbates Insulin Resistance During Diabetic Ketoacidosis in Pediatric Patients With Type 1 Diabetes
Authors: Elizabeth S. Keiner, James C. Slaughter, Karishma A. Datye, Alan D. Cherrington, Daniel J. Moore, Justin M. Gregory
Journal: Diabetes Care (2022)

OBJECTIVE Although mortality from coronavirus disease 2019 (COVID-19) among youth with type 1 diabetes is rare, severe acute respiratory syndrome coronavirus 2 is associated with increased pediatric hospitalizations for diabetic ketoacidosis (DKA). To clarify whether the relationship between COVID-19 and DKA is coincidental or causal, we compared tissue glucose disposal (TGD) during standardized treatment for DKA between pediatric patients with COVID-19 and those without COVID-19. RESEARCH DESIGN AND METHODS We retrospectively compared TGD during standardized therapy for DKA in all children with preexisting type 1 diabetes with or without COVID-19. Cases were assessed beginning with the first case of COVID-19–positive DKA on 19 June 2020 through 2 February 2022. RESULTS We identified 93 COVID-19–negative patients and 15 COVID-19–positive patients who were treated for DKA, with similar baseline characteristics between groups. Median TGD was 46% lower among patients who had COVID-19 compared with those who did not (P = 0.013). CONCLUSIONS These results suggest that COVID-19 provokes a metabolic derangement over and above factors that typically contribute to pediatric DKA. These findings underscore the significant and direct threat posed by COVID-19 in pediatric type 1 diabetes and emphasize the importance of mitigation and monitoring including through vaccination as a primary prevention.
Smart pH-responsive polyhydralazine/bortezomib nanoparticles for remodeling tumor microenvironment and enhancing chemotherapy
Authors: Rui Wang, Xiaodan Xu, Dongdong Li, Wei Zhang, Xueying Shi, Hongxia Xu, Jianqiao Hong, Shasha Yao, Jiwei Liu, Zhenli Wei, Ying Piao, Zhuxian Zhou, Youqing Shen, Jianbin Tang
Journal: Biomaterials (2022)
Efficacy and safety of topical brepocitinib for the treatment of mild-to-moderate atopic dermatitis: a phase IIb, randomized, double-blind, vehicle-controlled, dose-ranging and parallel-group study
Authors: Megan N. Landis, Mark Arya, Stacy Smith, Zoe Draelos, Lisa Usdan, Sanela Tarabar, Vivek Pradhan, Sudeepta Aggarwal, Christopher Banfield, Elena Peeva, Michael S. Vincent, Vanja Sikirica, Jason Xenakis, Jean S. Beebe
Journal: British Journal of Dermatology (2022)

Atopic dermatitis (AD) is a prevalent inflammatory, pruritic skin disease. The Janus kinase (JAK) pathway is a treatment target.To assess the efficacy, safety and pharmacokinetics of topical cream brepocitinib, a small-molecule tyrosine kinase 2 (TYK2)/JAK1 inhibitor, in participants with mild-to-moderate AD.In this phase IIb, double-blind, dose-ranging study, participants were randomized to receive one of eight treatments for 6 weeks: brepocitinib 0·1% once daily (QD), 0·3% QD or twice daily (BID), 1·0% QD or BID, 3·0% QD, or vehicle QD or BID. The primary endpoint was the percentage change from baseline in the Eczema Area and Severity Index (EASI) total score at week 6. Adverse events (AEs) were monitored.Overall, 292 participants were enrolled and randomized. The brepocitinib 1% QD and 1% BID groups achieved statistically significantly greater (with multiplicity-adjusted P < 0·05 due to Hochberg's step-up method) percentage reductions from baseline in EASI total score at week 6 [least squares mean (90% confidence interval, CI): QD: -70·1 (-82·1 to -58·0); BID: -75·0 (-83·8 to -66·2)] compared with respective vehicle [QD: -44·4 (-57·3 to -31·6); BID: -47·6 (-57·5 to -37·7)]. There was not a dose-dependent trend in AE frequency, and there were no serious AEs or deaths.Topical brepocitinib is effective and well tolerated in participants with mild-to-moderate AD. What is already known about this topic? Janus kinase (JAK) inhibitors are in development for treatment of atopic dermatitis (AD). The tyrosine kinase 2 and JAK 1 inhibition by brepocitinib may bring a new profile for topical JAK inhibitors for treatment of mild-to-moderate AD. What does this study add? Topical brepocitinib can provide rapid, effective symptom reduction, and could offer a novel alternative to current topical treatments for mild-to-moderate AD.
The microsomal prostaglandin E synthase-1/prostaglandin E2 axis induces recovery from ischaemia via recruitment of regulatory T cells
Authors: Hideki Amano, Koji Eshima, Yoshiya Ito, Masaki Nakamura, Hidero Kitasato, Fumihiro Ogawa, Kanako Hosono, Kazuya Iwabuchi, Satoshi Uematsu, Shizuo Akira, Shuh Narumiya, Masataka Majima
Journal: Cardiovascular Research (2022)

Abstract Aims Microsomal prostaglandin E synthase-1 (mPGES-1)/prostaglandin E2 (PGE2) induces angiogenesis through the prostaglandin E2 receptor (EP1–4). Among immune cells, regulatory T cells (Tregs), which inhibit immune responses, have been implicated in angiogenesis, and PGE2 is known to modulate the function and differentiation of Tregs. We hypothesized that mPGES-1/PGE2-EP signalling could contribute to recovery from ischaemic conditions by promoting the accumulation of Tregs. Methods and results Wild-type (WT), mPGES-1-deficient (mPges-1−/−), and EP4 receptor-deficient (Ep4−/−) male mice, 6–8 weeks old, were used. Hindlimb ischaemia was induced by femoral artery ligation. Recovery from ischaemia was suppressed in mPges-1−/− mice and compared with WT mice. The number of accumulated forkhead box protein P3 (FoxP3)+ cells in ischaemic muscle tissue was decreased in mPges-1−/− mice compared with that in WT mice. Expression levels of transforming growth factor-β (TGF-β) and stromal cell derived factor-1 (SDF-1) in ischaemic tissue were also suppressed in mPges-1−/− mice. The number of accumulated FoxP3+ cells and blood flow recovery were suppressed when Tregs were depleted by injecting antibody against folate receptor 4 in WT mice but not in mPges-1−/− mice. Recovery from ischaemia was significantly suppressed in Ep4−/− mice compared with that in WT mice. Furthermore, mRNA levels of Foxp3 and Tgf-β were suppressed in Ep4−/− mice. Moreover, the number of accumulated FoxP3+ cells in ischaemic tissue was diminished in Ep4−/− mice compared with that in Ep4+/+ mice. Conclusion These findings suggested that mPGES-1/PGE2 induced neovascularization from ischaemia via EP4 by promoting the accumulation of Tregs. Highly selective EP4 agonists could be useful for the treatment of peripheral artery disease.
Acute Respiratory Illness in an American Community
Authors: Arnold S. Monto
Journal: JAMA (1974)

Approximately 14,600 cases of respiratory illness in 4,905 residents of Tecumseh, Mich, were studied during a six-year period. The annual incidence of respiratory illness for each individual was calculated. Rates decreased with age except during the 20- to 29-year decade. In children less than 3 years of age, males experienced more illnesses than females; in those older than that, the reverse was true. Frequency of physician consultation varied with illness type. Rhinoviruses were the most frequently isolated pathogen from all illnesses. From those associated with physician consultation, group A hemolytic streptococci were nearly as frequently isolated. More illnesses started on Monday than on any other day of the week. Illness frequency increased with education of head of household, but decreased with family income. Therefore, highest rates were observed in more educated families with low income.